Tenofovir DF: A Promising Nucleotide Analog in Development

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Tenofovir DF (TDF) is an experimental nucleotide reverse transcriptase inhibitor being developed by Gilead Sciences of Foster City, CA. Nucleotide reverse transcriptase inhibitors are similar to nucleoside analog (NRTI) drugs such as d4T (Zerit) but do not require the same degree of processing within cells to become active (see full explanation below).

Recent news indicates that TDF, also known as bis-POC PMPA, may reduce levels of HIV RNA circulating in the bloodstream by more than 80%, and work effectively in persons who have displayed resistance to a wide variety of other anti-HIV medications -- particularly nucleoside analogs. This highly active compound also appears to cause very few side effects and can be taken once a day.

Preliminary Studies

Tenofovir DF is an oral prodrug of tenofovir, which first showed promise in 1995 when it was reported that the drug, then known simply as PMPA, was able to prevent simian immune deficiency virus (SIV, an animal model for HIV) infection in macaque monkeys (see also "Research Notes" in BETA, December 1995). In a subsequent Phase I/II trial using the TDF formulation as monotherapy, human subjects showed viral load reductions of up to 1.2 log copies/mL at a dose of 300mg.

Clinical Trial Data

Further investigations have been designed to assess the nucleotide analog in combination with other anti-HIV drugs. Extended interim results of a double-blind, placebo-controlled Phase II clinical trial were presented at the 7th Conference on Retroviruses and Opportunistic Infections (CROI), held January 30 to February 2, 2000, in San Francisco. (Twenty-four-week results had been presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC], held in September 1999 in San Francisco.) Known as Study 902, this 48-week investigation enrolled 189 HIV positive volunteers who were randomized to take one of three once-daily oral doses of TDF (75mg, 150mg, or 300mg) or placebo in addition to their existing antiretroviral regimen.

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To demonstrate TDF's efficacy in persons whose multidrug regimens did not completely control HIV replication, Robert Schooley, M.D., of the University of Colorado Health Sciences Center and colleagues chose trial subjects who had been taking highly active antiretroviral therapy (HAART) for a mean of over four years without optimal viral suppression. These extensively pretreated volunteers were required to be on a stable (unchanged) regimen of no less than four anti-HIV medications for at least eight weeks prior to trial entry while exhibiting detectable plasma HIV RNA (ranging from 400 to 100,000 copies/mL).

As reported by Dr. Schooley at the 1999 ICAAC, treatment with TDF was well tolerated at all three dose levels. Only 4.4% of the subjects taking the drug discontinued treatment, compared with 7.4% of those taking placebo. Serious adverse events were infrequent, and reported by only four people (7%) in the 300mg dose group compared with three people (11%) in the placebo group.

The drug's attractiveness was further underscored by its ability to reduce levels of HIV RNA in the trial subjects, all of whom were experiencing viral breakthrough (insufficient viral suppression) on their existing HAART regimens. Statistically significant viral load decreases were detected in each dose group.

At the 24-week interim follow-up, subjects receiving the 300mg dose of TDF displayed a median 0.75 log copies/mL decrease; at week 32, that rate had been maintained. Subjects in the 150mg and 75mg dose arms had viral load reductions of 0.40 log copies/mL and 0.45 log copies/mL, respectively. Based on these encouraging results, all subjects taking placebo were switched to the 300mg TDF treatment arm at week 24. At week 32, those in the 150mg, 75mg, and former placebo arms displayed similar HIV RNA reductions (approximately 0.5 log copies/mL). Twelve percent achieved an undetectable viral load based on ultrasensitive tests (limit of detection 50 copies/mL).

It should be noted that none of the treatment arms showed changes in CD4 cell counts at the ICAAC interim analysis; CD4 cell count levels were not reported at the 7th CROI.

Benefits of Early Treatment

There is also evidence that short-term treatment with TDF during the acute (early) stage of HIV infection may significantly delay the onset of AIDS in a monkey model. A report in the April 1999 issue of the Journal of Virology indicated that either 14 or 60 days' use of the drug in ten newborn, SIV-infected macaques was able to impede disease progression and boost immune responses without inducing drug-resistant viral strains. All macaques treated with TDF remained healthy for at least six months following the initiation of treatment at five days of age.

Since early events in both SIV and HIV infection appear to determine the ultimate course of disease, results from this study suggest that TDF may be able to suppress viremia during the initial stage of infection and, if necessary, later on (due to the absence of drug-resistant mutants).

Resistance Profile

Tenofovir DF's powerful anti-HIV activity stems in part from its unique resistance profile. While partial resistance to this nucleotide analog (as well as to abacavir [Ziagen] and ddI [Videx]) has been associated with the K65R mutation, TDF remains active against virus with the pivotal nucleoside analog Q151M mutation. Moreover, resistance to TDF appears to be reversed by the M184V mutation selected by 3TC.

The K65R mutation may have been due, however, to the presence of abacavir or ddI in these subjects' regimens. It could not be determined in this blinded analysis whether these three persons were taking TDF; nevertheless, none of them experienced HIV RNA rebound by week 24. Although 42 subjects (35%) displayed new NRTI-related mutations, other resistance mutations developed at low rates: 6% developed PI-related mutations and only 2% developed an additional NNRTI mutation. Novel (new) reverse transcriptase mutations were not detected in any of the 121 subjects. This drug is therefore likely to confer benefits in persons whose virus does not respond adequately to their current anti-HIV regimens.

Comparison with Adefovir Dipivoxil

Like nucleoside analogs, nucleotide analog drugs interfere with reverse transcriptase, the viral enzyme that normally allows HIV to translate its genetic material (in the form of RNA) into DNA. The presence of defective, synthetic nucleotides (the basic structural units of nucleic acids, such as RNA and DNA) causes premature termination of the viral DNA chain, thus preventing successful replication. Nucleotide analogs are potentially more effective than their nucleoside cousins in a wider range of cells because they are partially phosphorylated, or chemically preactived with an extra phosphate group. As a result, they are incorporated directly into a DNA chain more readily than nucleoside analogs, which must undergo triple phosphorylation inside living cells to be rendered active.

TDF has consistently shown more promise than the more widely known drug in its class, adefovir dipivoxil, another Gilead drug that was denied accelerated approval by the Food and Drug Administration (FDA) on November 1, 1999 (see "News Briefs," BETA, 1999 Year-End Special Edition). Adefovir had been stymied in the research pipeline and was subsequently downgraded by the FDA because of its nephrotoxicity, or damaging effect on kidney cells. TDF does not appear to be nephrotoxic in studies to date, nor does it deplete L-carnitine concentrations in the body like adefovir (L-carnitine is an amino acid that plays a major role in fat metabolism). Furthermore, adefovir -- which is still under investigation to treat hepatitis B virus (HBV) infection at a much lower dose -- displays less potent antiretroviral activity (e.g., viral load reductions of only 0.3-0.4 log copies/mL) compared with TDF.

Future Outlook

Gilead Sciences, building on the encouraging data presented at the 39th ICAAC, launched a multinational, Phase III clinical trial in late 1999 to show that TDF's activity against multidrug-resistant HIV can be sustained. Despite the fact that the drug will not become available for at least another year, it is well worth watching the clinical progress of this potential addition to the anti-HIV arsenal. For information regarding enrollment in Gilead Sciences' Tenofovir Compassionate Access Study, call 800-276-0231.

A note from TheBody.com: The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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